RT Journal Article
SR Electronic
T1 CYP1A1 and CYP1B1 in Blood-Brain Interfaces: CYP1A1-Dependent Bioactivation of 7,12-Dimethylbenz(a)anthracene in Endothelial Cells
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 259
OP 265
DO 10.1124/dmd.31.3.259
VO 31
IS 3
A1 Granberg, Lizette
A1 Östergren, Anna
A1 Brandt, Ingvar
A1 Brittebo, Eva B.
YR 2003
UL http://dmd.aspetjournals.org/content/31/3/259.abstract
AB Immunohistochemistry and autoradiography were used to identify sites of the cytochrome P450 enzymes (P450) 1A1 and 1B1 expression and activation of 7,12-dimethylbenz(a)anthracene (DMBA), in the brain of rodents pretreated with the aryl hydrocarbon receptor (AhR) agonists β-naphthoflavone (BNF), 3,3′,4,4′,5-pentachlorobiphenyl or vehicle. Immunohistochemistry revealed that CYP1A1 was preferentially induced in endothelial cells (EC) in the choroid plexus, in veins in the leptomeninges, and in cerebral veins of AhR agonist-pretreated mice. No induction occurred in cerebral capillary EC. In vehicle-treated mice no localization of CYP1A1 in EC was observed. CYP1B1 was expressed in smooth muscle cells of arteries in the leptomeninges, in cerebral arteries/arterioles and to a low extent in ependymal cells of AhR agonist- and vehicle-treated mice. No CYP1B1 was detected in capillary loops of the choroid plexus or in cerebral capillaries. Following administration of [3H]DMBA to BNF-pretreated mice, a marked irreversible binding in EC of the choroid plexus and of veins in the leptomeninges was observed but not in cerebral capillaries. In vehicle-treated mice, there was no [3H]DMBA-binding at these sites. Furthermore, a high level of irreversibly bound [3H]DMBA occurred in EC at these sites in precision-cut mouse/rat brain slices and in excised blood-brain interfaces incubated with [3H]DMBA. Since [3H]DMBA binding sites corresponded with the sites of CYP1A1 induction, we conclude that rodents express a constitutively low but highly inducible and functional CYP1A1 in EC of some of the blood-brain interfaces. The role of CYP1A1/1B1 and environmental pollutants in the etiology of cerebrovascular disease needs further consideration. The American Society for Pharmacology and Experimental Therapeutics